Biomedical Engineering Reference
In-Depth Information
anti-CD40 caused a significant weight loss in mice for several days after initia-
tion of therapy.
115
On the other hand, the anti-CD40-liposomes treatment did not
cause significant weight loss relative to PBS-treated controls at any time point.
115
Circulating serum levels of IL-6 provided indication of systemic inflammation
in response to immunostimulant therapy. The anti-CD40 that was intratumor-
ally injected caused a significant increase in serum IL-6 within 24 h but the anti-
CD40-liposomes induced levels in serum were insignificant compared with the
control mice. The studies of Kwong indicated the potential benefits of liposome
anchoring but it inhibited the anti-tumor efficacy of anti-CD40 monotherapy.
The anti-tumor efficacy of liposomal combination anti-CD40/CpG in the
B16 model showed a delay in tumor growth compared to untreated animals but
eventually all succumbed.
115
The combination of soluble CpG with soluble anti-
CD40 provided only a modest enhancement over soluble anti-CD40 alone. No
significant difference in survival benefit was observed between either regimen
of soluble therapy (
p
= 0.33, n.s. by log-rank test).
In contrast, the liposomal anti-CD40/CpG showed a significant increase in
the time to progression for partial responders from a mean of 27.8 ± 1.4 days
for soluble treatment to 33.4 ± 1.8 days for liposomal anti-CD40/CpG.
115
The
liposome-anti-CD40/CpG therapy prolonged the survival of tumor-bearing
mice and exhibited a longer survival period. Additionally, the combinatorial
liposome therapy demonstrated a significant increase in potency compared with
liposomal anti-CD40 alone.
115
A synergistic effect in the particle-mediated co-
delivery of both immunostimulants can be inferred from these observations.
The use of biomaterial systems for the local delivery of anti-CD40, CpG,
and immunomodulatory cytokines have been described using liposomes and
NPs to larger microspheres and hydrogels. A variety of biomaterial carriers
demonstrated significant anti-tumor effects of IL-2, IL-12, and/or GM-CSF
in therapeutic challenge models, but the systemic inflammatory effects were
not examined.
204,205,208
In the setting of prophylactic vaccinations (or pre-
tumor challenge), Hatzifoti et al.
209
demonstrated that liposomal entrapment
decreased anti-CD40-induced toxicity (as measured by splenomegaly), while
another study
200
showed that subcutaneous injection of cationic gelatin NMs
complexed with CpG DNA and vaccine antigens reduced systemic cytokine
induction relative to soluble injections of the agonist (via decreased systemic
exposure to nanoparticle-bound CpG compared to unencapsulated CpG).
115
In another study, when De Jong et al.
203
used liposomes to encapsulate CpG
DNA they found that subcutaneous liposomal delivery significantly increased
plasma levels of inflammatory cytokine compared with subcutaneous free CpG.
These observations might reflect differences in the stability of agonist entrap-
ment in the various carriers since soluble drugs or immuno-agonists released
from locally-injected carriers have been shown to reach the systemic circulation
as early as 6 h post-injection.
202,205
These observations amplify the benefits of
physically anchoring immunomodulatory compounds to the carriers compared
to more commonly used encapsulation/release strategies.
115
